Abstract:

Background and Objectives—
Dipeptidyl peptidase-4 (DPP4) inhibition is a potential strategy
to increase the engraftment rate of hematopoietic stem/progenitor cells. A recent clinical trial
using sitagliptin, a DPP4 inhibitor approved for type 2 diabetes mellitus, has shown to be a
promising approach in adults with hematological malignancies after umbilical cord blood (UCB)
hematopoietic cell transplant (HCT). Based on data from this clinical trial, a semi-mechanistic
model was developed to simultaneously describe DPP4 activity after multiple doses of sitagliptin
in subjects with hematological malignancies after a single-unit UCB HCT.
Methods—
The clinical study included 24 patients that received myeloablative conditioning
followed by 4 oral sitagliptin 600mg with single-unit UCB HCT. Using a nonlinear mixed effects
approach, a semi-mechanistic pharmacokinetic/pharmacodynamic model was developed to
describe DPP4 activity from this trial data using NONMEM 7.2. The model was used to drive
Monte-Carlo simulations to probe various dosage schedules and the attendant DPP4 response.
Results—
The disposition of sitagliptin in plasma was best described by a 2-compartment model.
The relationship between sitagliptin concentration and DPP4 activity was best described by an
indirect response model with a negative feedback loop. Simulations showed that twice a day or
three times a day dosage schedules were superior to once daily schedule for maximal DPP4
inhibition at the lowest sitagliptin exposure.
Conclusion—
This study provides the first pharmacokinetic/pharmacodynamic model of
sitagliptin in the context of HCT, and provides a valuable tool for exploration of optimal dosing
regimens, critical for improving time to engraftment in patients after UCB HCT.